Residual tumor deposits missed by conventional treatments frequently seed local and distal recurrence utilizing a network of molecular signaling mechanisms. Beyond providing contrast for molecular-guided surgery, this talk will highlight new concepts in phototherapy to address residual cancer cells in danger zones of recurrence, including selective treatment of microscopic disease using molecular-targeted, activatable immunoconjugates, and photo-initiated release of multikinase inhibitors that suppress multiple modes of tumor escape using optically active nanoparticles. These new approaches support an expanded role for the use of light in fluorescence-guided surgery—for phototherapy and for focused drug release to maximize tumor debulking with suppression of disease recurrence.